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EC number: 281-161-6 | CAS number: 83877-91-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: inhalation
Administrative data
- Endpoint:
- sub-chronic toxicity: inhalation
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- The study was conducted in compliance with GLP but guideline followed was not mentioned. Read-across justification: The substance is hydrolytically unstable. When it comes in contact with water or moisture complete hydrolysis will take place with no significant reaction products other than alcohols, ethyl acetoacetate and hydrated titanium dioxide. The half-life of hydrolysis is < 10 minutes @ 25 ˚C. This rapid hydrolysis is the driving force for the toxicokinetics of target substance. Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the most hazardous degradation products released from the target substance. In addition, because of rapid hydrolysis the dermal effects of the target substance are similar to the irritating properties of the degradation products. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the mixture of particular alcohol and ethyl acetoacetate which might change the hazardous properties of the target substance compared to the properties of the pure alcohol and ethyl acetoacetate. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across from the most hazardous degradation products (alcohols) to evaluate irritation, sensitization and the short-term and long-term toxicological effects of the target substance.
Data source
Reference
- Reference Type:
- publication
- Title:
- Neurotoxicity evaluation of rats after subchronic inhalation exposure to isobutanol
- Author:
- Li, A.A., Thake, D.C., Kaempfe, T.A., Branch, D.K., O’Donnell, P., Speck, F.L., Tyler, T.R., Faber, W.D., Jasti, S.L., Ouellette, R., and M.I. Banton
- Year:
- 1 999
- Bibliographic source:
- Neurotoxicology, vol 20(6) PN. 889-900
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- No details are provided in the reference concerning the method employed.
- GLP compliance:
- no
Test material
- Reference substance name:
- 2-methylpropan-1-ol
- EC Number:
- 201-148-0
- EC Name:
- 2-methylpropan-1-ol
- Cas Number:
- 78-83-1
- Molecular formula:
- C4H10O
- IUPAC Name:
- 2-methylpropan-1-ol
- Test material form:
- other: liquid
- Details on test material:
- - Name of test material (as cited in study report): Isobutanol
- Analytical purity: 99%
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source:Charles river laboratories, Inc.;raleigh,NC
- Age at study initiation:8 weeks
- Weight at study initiation:285-365 g males, 170-242 g females
- Fasting period before study:
- Diet (e.g. ad libitum): purina mills rodent chow #5002
- Water (e.g. ad libitum):ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C):18-26
- Humidity (%):30-70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):12 hrs
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- other: glass hazelton H-2000 chamber
- Vehicle:
- air
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:glass hazelton H-2000 chamber
- Temperature, humidity,in air chamber: 23-24 ̊C, 48-53 % respectively
- Air flow rate: 500 liter/min
- Air change rate: 15 air changes /min
TEST ATMOSPHERE
- Brief description of analytical method used: isobutanol vapor were determined by drawing test atmosphere samples from animals breathing zoneat evenly spaced interval (18 sample per exposure) through Fourier transform infrared analyzer (FVB/analect, Irvine, CA)
- Samples taken from breathing zone: yes - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The mean (±SD) isobutanol chamber concentration were 258 (±8), 1044(±34), and 2548 (±58) ppm for the duration of the subchronic neurotoxicity study. The respective nominal to analytical ratio were .97, .95 and .97. For SCOB ( Schedule controlled operant behavior ) study isobutanol chamber concentration were 258 (±9), 1045(±35), and 2557 (±60) ppm and the nominal to analytical ratio were .97,.96 and .97 respectively.
- Duration of treatment / exposure:
- 14 weeks with the exception that the animals were not exposed one day during 4th, 8th and 13th week of exposure when animals were subjected to neuro behavioral study. Each rats received at least 70 exposures.
- Frequency of treatment:
- 6hrs/day
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0,250,1000,2500 ppm
Basis:
no data
- No. of animals per sex per dose:
- 15 animals per group per sex (both male and female) for neurotoxicity study (Total 120 animals)
10 male SD rats per group for SCOB (Schedule controlled operant behavior) study (total 40 rats) - Control animals:
- yes
- Positive control:
- Positive control group study (with amphetamine SO4 and chlorlpromazine) was conducted with separate groups of rats (4 group of 10 male SD rats each) prior to this study to demonstrate 4FR20/2FI120 multiple schedule of reinforcement generates response rate.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule:Twice a day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: during 14th exposure week in neurotoxicity study
- Dose groups that were examined: control and highest dose group(2500 ppm)
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the termination of study
- Anaesthetic used for blood collection: Yes (CO2)
- Animals fasted: Yes (overnight)
- How many animals: 5 rats/sex/exposure group
.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:at the termination of study
- Animals fasted: Yes
- How many animals:5 rats/sex/exposure group
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: prior to exposure and then on 4th, 8th, 13th weeks of exposure
- Dose groups that were examined: all groups
- Battery of functions tested: Functional observation battery (FOB) and motor activity
OTHER: - Sacrifice and pathology:
HISTOPATHOLOGY: Yes- Other examinations:
- Behavioral test consist of Functional observation battery (FOB) and an automated test for motor activity. FOB test include observation to degree of lacrimation, salivation, presence of exopthalmia, degree of palpebral opening, presence or absence of piloerection and any general descriptive clinical effects were noted. Motor activity was measured by automated photo cell recording apparatus designed to measure activity in the novel enviroment.
- Statistics:
- Total motor activity and SCOB(Schedule controlled operant behavior) dependent variables were analyzed as mean weekly percent of protest values at each time point using Dunnetts 2 sided comparision of treatment and control and Levene's test for homogencity of variance. In addition two factor repeated measure analysis of co-variance (REPANCOVA) used for motor and SCOB dependent variable.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- There were no treatment related abnormal clinical sign seen after exposure to any concentration
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- There were no treatment related abnormal clinical sign seen after exposure to any concentration
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- There were no treatment related significant changes in body weight and cumulative body weight were seen after exposure to any concentration
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- There were no treatment related significant food consumption changes were seen at any dose
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- No occular abnormalities noted at 2500 ppm and control exposure levels.
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- There were slight increases in RBC, heamatocrit value and heamoglobin parameters in 2500 ppm females that were statistically significant.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- There were increase in serum calcium level in the males at 100 ppm significantly but that was not in dose related fashion, so can not be considered as a consequence of isobutanol exposure.
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- There were no significant concentration time interaction in any behavioral parameters as determined by repeated measures analysis of covariance
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- there were no significant difference in terminal absolute organ weight, organ to body weight ratio, or organ to brain weight ratio for any group or for any tisssue.
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- There were no treatment related gross or microscopic abnormalities noted in any of the tissue
- Details on results:
- Ther were no significant effects of isobutanol exposure to all concentration were observed for clinical signs and mortality, body weight and weight gain, organ weights, food consumption, food efficiency, water consumption, ophthalmoscopic examination.
HAEMATOLOGY: There were slight increases in RBC, heamatocrit value and heamoglobin parameters in 2500 ppm females that were statistically significant.(see picture below)
NEUROBEHAVIOUR : During SCOB (Schedule controlled operant behavior) analysis FR post-reinforcement pause (PSAP), FR running rate, FI response rate, FI Index of curvature (IOC) were determined. There were no statistically significant effects between treated and control groups for any SCOB parameters. (see picutre below)
Effect levels
- Dose descriptor:
- NOAEC
- Effect level:
- 3 030 mg/m³ air
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: There were slight increases in RBC, heamatocrit value and heamoglobin parameters in 2500 ppm females that were statistically significant. Thus, the NOAEC of this substance is 1000 ppm (3030 mg/m3)
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Read-across justifications and data matrices are presented in IUCLID section 13.
Applicant's summary and conclusion
- Conclusions:
- The study consisted of male and female ad libitum-fed Sprague-Dawley(SD) rats designated for functional observational battery, motor activity, and
neuropathology endpoints. Groups consisted of 20, 10, 10, and 20 rats/sex for the 0, 250, 1000, and 2500 ppm groups, respectively. Based on the study results the NOAEL of 1000 ppm (3030 mg/m3) was established. - Executive summary:
There were no morphological of behavioural effects indicative of a persistent or progressive effect of 2 -methylproanol on the nervous system at exposure concentrations of up to 2500 ppm. A slight reduction in responsiveness to external stimuli occurred in all treated groups during exposure. However, there was no difference from the control animals with respect to responsiveness during nonexposure periods. No effects were noted during the FOB examinations. Therefore, the slight decrease in responsiveness are likely transient effects from acute exposure to 2 -methylpropanol. There was a slight (but statistically significant) increase in red blood cell counts, hematocrit, and hemoglobin parameters in the 2500 ppm female rats when compared to the control female rats. Although these effects were considered related to treatment and considered for the derivation of the NOAEL, they were of questionable biological significance
due to the slight nature of the effects. There were no changes in ophthalmology, serum chemistry, organ weights, or gross or microscopic
pathology that were attributed to 2 -methylpropanol exposure.
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